Ester of 3,4-dihydroxy-alpha (isopropylamino) methyl benzyl alcohol, composition and anti-asthma use thereof

ABSTRACT

A novel ester of the formula:   AND THE NON-TOXIC PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF. The compound evidences increased stability and lipoidal solubility and is extremely valuable in the treatment of conditions responsive to sympathomimetic agents and especially the management of bronchial asthma.

United States Patent [191 Hussain et al.

[4 1 Feb. 25, 1975 ESTER OF 3,4-DIHYDROXY-ALPHA (ISOPROPYLAMINO) METHYLBENZYL ALCOHOL, COMPOSITION AND ANTI-ASTHMA USE THEREOF [75] Inventors:Anwar A. Hussain; James E.

Truelove, both of Lawrence, Kans.

[73] Assignee: Interx Corporation, Lawrence,

Kans.

[22] Filed: Nov. 22, 1972 [21] App]. No.: 308,771

OTHER PUBLICATIONS Bretschneidcr Monatsh, vol. 77 (I947). pp. 385-97.

Primary Examiner-James A. Patten Attorney, Agent, or Firm-Norman H.Stepno; Charles N. Blitzer [57] ABSTRACT A novel ester of the formula:

and the non-toxic pharmaceutically acceptable acid addition saltsthereof. The compound evidences increased stability and lipoidalsolubility and is extremely valuable in the treatment of conditionsresponsive to sympathomimetic agents and especially the management ofbronchial asthma.

8 Claims, N0 Drawings ESTER OF 3,4-DIHYDROXY-ALPHA (ISOPRORPYLAMINO)METHYL BENZYL ALCOHOL, COMPOSITION AND ANTI-ASTHMA I USE THEREOFBACKGROUND OF THE INVENTION and its pharmaceutically acceptable,non-toxic acid addition salts. The compound and its salts are useful asa broncholytic agent, and can be administered per se or in the form of acomposition comprised of the compound of the invention and apharmaceutically acceptable carrier therefor.

isoproterenol is a well-known sympathomimetic amine which acts almostexclusively on the [3 receptors or postganglionic adrenergic nerves inthe sympathetic nervous system and, therefore, the administration ofisoproterenol generally produces, among other things, a cardiacexcitatory action manifested by tachycardia, palpitation and an increasein the force of contraction of the heart muscle, dilation of vascularbeds supplying skeletal muscle, and relaxation of bronchial muscle. As

a consequence of the foregoing, isoproterenol is clinically significantas a bronchodilator in respiratory disorders such as bronchial asthma,and as a cardiac stimulant in heart bloc. However, a number of inherentdisadvantages are associated with this prior art compound which havesubstantially precluded the widespread acceptance of isoproterenol inits principal field of use as a bronchodilator.

One of these disadvantages is the action on the heart referred to abovewhich in certain instances is the desired pharmacological response, butwhen isoproterenol is to be utilized in the treatment of bronchialasthma it is usually employed in large doses in the form,

of an inhalation mist and as a result the normally slight cardiac actionofthe drug is accentuated to such an extent that the resultanttachycardia and palpitation'become undesirable side effects. Anotherdisadvantage with the prior art compound is its instability to both airand light. as well as to chemical attack by many agents that areconventionally used in pharmaceutical preparations. Past attempts by theprior art to overcome the problem of instability have not met with anyacceptable success. One such attempt involved acidifying solutionscontaining the drug which solutions were then irritating to body tissue,and if these solutions were later adjusted 2 to a physiological pH, thefree drug frequently precipitated resulting in the deterioration of theproduct. it has also been suggested to protect the drug againstoxidative deterioration by the addition of the anti-oxidant sodiumbisulfite to a solution containing the drug. it was found, however, thatthis anti-oxidant chemically attacked the aliphatic side chain of thedrug to form a biologically inactive derivative thereof. Moreover, theprior art 3,4-dihydroxy-a-[(isopropylamino)methyl] benzyl alcoholsuffered from the disadvantage of negligible lipoid solubilityattributed to its hydrophilic phenolic hydroxyl groups which tended torestrict the medical application of the drug. Therefore, there exists animmediate and pressing need for a new and useful phar- (Formula 1)maceutical compound that possesses therapeutic properties useful fortreating bronchial asthma, while remaining essentially free from theunwanted disadvantages associated with the prior art compounds.

SUMMARY OF THE lNYENTlON Accordingly, it is an immediate object of thisinvention to provide a novel pharmaceutical compound and .its acceptableacid addition salts that are useful for treating bronchial asthma and asa-sympathomimetic agent.

Another object of the invention is to provide a novel and useful esterof 3,4-dihydroxy-a-[isopropyl)- methyl]benzyl alcohol and its acceptablesalts that are essentially free from the unwanted effects associatedwith the prior art.

Still another object of the invention is to provide a new and useful3,4-dipivaloxy-a- [(isopropylamino)methyl] benzyl alcohol that possessesincreased stability and solubility and can be administered inconventional pharmaceutical formulations.

Yet still another object of the invention is to provide the compound3,4-dipivaloxy-a-[(isopropylamino)methyl]benzyl alcohol as a usefultherapeutic agent that has improved lipoid solubility for enhancedresorption when administered to warm-blooded animal tissues.

Another object of the invention is to provide3,4-dipivaloxy-a-[isopropylamino)methyl]benzyl alcohol that can beadministered per se or can be dispensed in aerosols and other types ofpharmaceutical formulations to warm-blooded animals to produce a localor systemic physiological or pharmacological beneficial effect. Otherobjects, features and advantages of the invention will be apparent tothose skilled in the art from the detailed description of the inventionwhich follows, taken in conjunction with the accompanying claims.

DETAILED DESCRIPTION OF THE INVENTION aqueous media to yield the producta -ispropylamino- 3,4-dipivaloxy acetophenone. ln attaining the objects,features, and advantages of The aliphatic side chain keto functionalityis convethe present invention, it has now been found that the nientlyreduced to the corresponding alcohol group compound embraced by Formula1 g 5 very smoothly and in good yield by the catalytic hydro- OH H(Formula 1) and its pharmaceutically acceptable salts possessheregenation of the a -isopropylamino-3,4-dipivaloxy acetofore unknownadvantageous properties and are extophenone. Generally, thehydrogenation is carried out tremely valuable in the management ofbronchial in the presence of a metal catalyst such as platinum, asthma,and for use as a general sympathomimetic palladium, rhodium, platiniumoxide and the like. The agent that acts on postganglionic adrenergicnerve endreduction of the ketone in a hydrogen environment is ings andstructures innervated by them and further usually conducted at about 1atmosphere to 3 atmocharacterized by an enhanced rate of absorptionwhile spheres and at room temperatures, or with heating simultaneouslyovercoming the problems associated from about 20C to 75C. The catalytichydrogenation with prior art isoproterenol compounds. is usually carriedout in a standard Parr vessel, or the The novel 3,4-dipivaloxyalike. Thecarbonyl can also be reduced by standard [(isopropylamino)methyl] benzylalcohol of this invenmethods such as metal hydride reduction, and thelike. tion, which can also be conveniently named l-(3,4- ModernSynthetic Reactions, by House, H. 0., pages 1dipivaloxyphenyl)-2-(isopropylamino)ethanol or 3,4- to 22, 1965,published by W. A. Benjamin, Inc., New dipivaloxyll-hydroxy-2-(isopropylamino)ethyl]- York. benzene is prepared by firstcontacting and reacting an 1 The resolution of the racemate can beaccomplished a-halo-3,4-dihydroxyacetophenone with stoichiometout byconventional standard resolution methods well ric amounts, usually withan excess of the alkylamine; known to those in the art as described inOrganic for example, with about 3 to 4 or more molecular Chemistry, byFieser and Fieser, pages 270 to 281, equivalents of the alkylamine foreach reactive halogen 1944, published by D. C. Heath and Company,Boston;

moiety present in the a-halo-3,4- and, Organic Chemistry, by Morrisonand Boyd, pages dihydroxyacetophenone present as a reactant. The re- 231to 233, 1969, published by Allyn and Boston, lnc., action is carried outin the presence of a suitable sol- Boston.

vent, at a temperature of about 10C to about 75C, The phrases,pharmaceutically acceptable" and and at atmospheric pressure, or higherpressures of non-toxic, acid addition salts as used herein generfrom 1to about 10 atmospheres and the like. The reacally includes thenon-toxic acid addition salts of the tants begin to react on contact,but it is generally prefcompounds of Formula 1, formed with non-toxicinorerable to carry out the reaction for about 10 minutes ganic ororganic acids. For example, the salts include to about one hour toproduce from the starting materithose derived from inorganic acids suchas hydrochloals the corresponding product, tx-isopropylamino-3,4- ric,hydrobromic, sulfuric, sulfamic, phosphoric, nitricdihydroxyacetophenone. and the like; and the salts prepared from organicacids Next, the hydroxyl groups of the product a-isosuch as acetic,propionic, succinic, glycollic, stearic,propylamino-3,4-dihydroxyacetophenone at positions lactic, malic.tartaric. i ri a ic. pam i mal i C-3 and C-4 of the aryl ring areesterified by reacting hydroxymaleic, phenylacetic, glutamic, benzoic,salian acylating agent with the hydroxyl group in an orcylic,sulfanilic, furmaric, salicyclic, toluenesulfonic, ganic medium.Examples of acylating agents suitable and the like. for esterifying thehydroxyl groups include anhydrides, The pharmaceutically acceptable acidaddition salts mixed anhydrides, the chloride of the appropriate alkaofthe present invention can be synthesized from the noic acid, and thelike. The acylation is carried out by compound embraced by Formula 1 byconventional, contacting and reacting the hydroxyl groups with, forchemical methods. Generally, the salts are prepared by example, an acidchloride pivalyl chloride, in the presreacting the free base withstoichiometric amounts or ence of a solvent, at a temperature of about5C to with an excess thereof of the desired salt-forming inor- 100C,usually at refluxing temperature, and at a presganic or organic acid ina suitable solvent or various sure of 1 atmosphere or higher, for about2 hours to 24 combination of solvents. For example, the free base hoursor longer. Generally, the reactants are present in can be dissolved in amixed aqueous solution of the apequivalent amounts or in excess thereof,for example, propriate acid and the salt recovered by standard tech- 2to 10 moles of acid chloride to 1 mole of hydroxyl reniques, forexample, by evaporation of the solution. Alactant. The acylated productis recovered by precipiternatively, the free base can be charged into anortating with an organic solvent, followed by convenganic solvent suchasa lower alkanol,asymmetrical or tional organic extraction andreprecipitation with an unsymmetrical ether containing 2 to l0 carbonatoms,

an alkyl ester, or mixtures thereof, and the like, and then it istreated with the appropriate acid to form the corresponding salt. Thesalt is recovered by standard recovery techniques, for example, byfiltration of the 'reaction and is converted to the hydrochloride salt,

Compound 2, by addition of the minimal amount of concentratedhydrochloric acid to give an acid solution. Overnight refrigerationprecipitates the product desired salt on spontaneous separation from theh 5 salt which is recovered by addition of 500 m1 acetone tion, or itcan be precipitated by the addition of 501- and filtration. Theresulting crystalline product has vent in which the salt is insolubleand recovered there- -P- and is ed th ut f rther purificafrom. tion.

Examples of suitable inorganic and organic solvents Next, 0-125 mole ofCOmPOImd 2 iS di OIVBd in 250 for performing the various reactionsinclude any inor- 10 ml ethyl acetate and 0.125 mole perchloric acid asa 70 ganic or organic solvent that does not adversely affect percentaqueous solution is slowly added thereto with the reactants or theresulting product including haloge- Continuous stirring. Then, an excessof pivalyl chloride, nated solvents such as methylene chloride,chloroform, Compound 3, 280 iS added and the xt e sl wly carbontetrachloride, ethylene chloride, ether solvents ar ed to reflutemperature. The reaction mixture is such as diethyl ether, dimethylether, and other solrefluxed for about 5 hours and allowed to cool toroom vents such as tetrahydrofuran, dioxane, diglyme, ntemperature withcontinuous stirring. The product is hexane, cyclooctane, benzene,heptane, cyclohexane, precipitated as the perchlorate salt by theaddition of and mixtures thereof, and like aliphatic, cycloaliphatic 500ml ether. The product, Compound 4, is isolated and aromatic hydrocarbonsolvents, water, acidified and purified by dissolution in minimalboiling acetone, aqueous solutions, mixed organic and inorganicsoluaddition of hexane to incipient turbidity, and precipitations, ethylacetate, propyl acetate, and the like. tion by overnight refrigeration.

The following examples are set forth as representa- Then, to 20 grams ofCompound 4 dissolved in 200 tive methods illustrative of the spirit ofthe present inml 95% ethanol in a Parr reaction vessel is added 1.5vention. These examples are not to be construed as limgrams Adamscatalyst, platinum oxide, and the mixture iting the scope of theinvention as other functionally hak under hydrog at 50 psi for 1 hour atambient equivalent means will by readily appare to those temperature.The mixture is then filtered and the ethaskilled m the sub ect art inthe light of the present speced o a st nd rd otary evaporator Thereification and the p y g clalmssulting oil is dissolved in 200 mlwater; the solution is neutralized with ammonium hydroxide and extractedEXAMPLE 1 Q exhaustively with chloroform. The combined chloro- Synthesisof 3,4-dipiva1oxy-aform extracts are dried over calcium chloride,filtered, [(isopropylamino)methyl] benzyl alcohol. First, in an andevaporated. The residue is dissolved in 200 ml adaptation of the methodof Corrigan et al; J. Am. ether and the product, Compound 5,precipitated as Chem. Soc, 71, 530-1 (1949), a mixture of 0.20 moles thehydrochloride salt by introduction of excess gasea-ch1oro-3,4-dihydroxyacetophenone, Compound 1, ous hydrogen chloride.The product is purified by dis- O.66 moles isopropylamine, and 125 mlisopropanol is solution in minimal boiling acetone, addition of hexaneheated with stirring to 75C, maintained at 75C for 5 to incipientturbidity, and overnight refrigeration. The minutes, then allowed tocool to room temperature crystalline material thus obtained has m.p.1535C. with stirring. The crude product separates during the Thissequence is outlined below.

0 i P H H E HQ]. CH CZ. "1' (CH3) ZCHNHZ GHZNHCH 2 'HCJ- Ho Ho Compound1 Compound 2 CH C CO HC104 3 3 CH NHCH(CH -Hc1o1 +(CH C C C 1 0 ll (cn cc-o Compound 3 Compound 4 0 TH (CH C C O CH Hg/Pt a1 uHcH(cH -Hc1 HCl 0(CH C C Compound 5 7 8 EXAMPLE 2 chloride vehicles, isotonic sodiumborate vehicles. and

the like.

The reaction procedure of Example 1 leading to Exemplary of a typicalmethod for preparing a solu- 3, p y- -l( p py mino)methyllbenzyl 2 1-tion to be used with conventional nebulizers containing cohol can alsobe carried out by optionally starting with 5 3,4-dipivaloxy-a-[(isoprypylamine)methyllbenzyl alcommercially available cateehol.Compound 6 below, cohol salt, sodium chloride, chlorobutanol, oximesulreacting it with stoichiometric amounts, usually a slight fate anddistilled water is as follows: first a measured excess of chloroacetylchloride, Compound 7. The inquantity of chlorobutanol is dissolved in500 milliliters termediate chloroacetyl catechol, Compound 8, is then ofdistilled water with stirring and optionally using genreacted withmethylamine HN CH Compound 9, and tle heat to form a solution. Then,sodium chloride, the reaction then is carried through the remainingprooxime sulfate and 3,4-dipivaloxy-a -[(isopropylamino)- cedure ofExample 1 to give the product. The starting methyl]benzyl alcoholhydrochloride is added and the reaction of Example 2 is as follows:solution stirred until clear. Next, distilled water is on OH 0 ClCCH C1Ho H Z Compound 6 Compound 7 Compound 8 NH CH Repeat Example 1 Compound9 The novel compound and its pharmaceutically acadded to the liter markand the solution filtered ceptable salts can be used by thepharmaceutical and through a conventional filter having an 0.2 to 0.4mithe veterinary arts for treating bronchial asthma includ- Cr n poreSize. The solution Will have a shelf-life stabiling hay fever andallergic rhinitis in a variety of phari y 0f3 years at 4C and itscompositional form as folmaceutical preparations. The new compound andits lo SI non-toxic salts are thus administrable in the form of in-Ingredients Per Liter. gmv

JCCIZlblCS, solutions, suppositories, omtments, emulsions, jellies,buccal patches, oral inhalants, nasal inha-3,4-dipivaloxy-a-[(isopropylamino) lants, aerosols, and in othersuitable forms. The phar- "F W almho' 40 Sodium chloride 8.0

maceutical or veterinary preparation which contains Chlorobutanol 5.0

the compound is conveniently admixed with from 2 sulfate 9- Distilledwater qs. I in r about 0.l micrograms to 10 grams of a non-toxicpharmaceutical organic or inorganic carrier. Typical of pharmaceuticallyacceptable carriers are, for example, A second pharmaceuticalformulation similar to the water, mixtures of water and water-misiciblesolvents formulation prepared immediately above is made by such as loweralkanols or aralkanols, vegetable oils, p0 following that procedureexcept that the amount of 3,4-

lyakylene glycols, petroleum based jelly, ethylcelludipivaloxy-a-[(isopropylamino)methyl]benzyl alcohol lose, ethyloleate, carboxymethylcellulose, polyvinylhydrochloride is increased to10 grams and 2% phenylpyrrolidone, isopropyl myristate and otherconventionethyl alcohol is used as the preservative.

ally employed acceptable carriers. The pharmaceutical A novellyophilized pharmaceutical preparation for preparation may also containnon-toxic auxiliary subsubsequent reconstitution immediately beforetherastances such as emulsifying, preserving, wetting agents, peuticadministration is prepared as follows: first, 4 bodying agents and thelike, as for example, polyethylgrams of 3,4-dipivaloxyene glycols 200,300, 400 and 600, carbowaxes 1,000, a-[(isopropylamino)methyllbenzylalcohol hydrochlol,500, 4,000 and 10,000, bacterial components such asride and 8 grams of mannitol U.S.P. are mixed with agiquaternaryammonium compounds, phenylmercuric tation into 1 liter of distilledwater and the solution salts known to have cold sterilizing propertiesand formed filtered through a sterile filter. Then, 5 cc to 12 which arenon-injurious in use, thimerosal, propyl cc of the solution istransferred to amber vials and lyparaben,buffcring ingredients such assodium chloride, ophilized by conventional methods until the freshlysodium borate, sodium acetate, gluconate buffers, and forming cake isdry. The lyophilized, dry cake is reconother conventional ingredientssuch as sorbitan monostituted with 10 cc of a diluent containing thefollowlaurate, thiethanolamine oleate, polyoxyethylene sorbiing: 2 gramssodium chloride, 5 grams of chlorobutatan monopalmitylate, dioctylsodium sulfosuccinate, nol, 0.1 gram of oxime sulfate, mixed withdistilled monothioglycerol, thiosorbitol, ethylenediamine tetrawater tothe volume line in a 1000 milliliter volumetric cetie acid, and thelike. Additionally, suitable vehicles flask.

can be used as carrier media for the present purpose The lyophilizedcake can optionally be prepared by including conventional phosphatebuffer vehicle sysreplacing the mennitol with buffering agents such as atems, isotonic boric acid vehicles, isotonic sodium mixture of sodiumchloride and sodium dihydrogen phosphate, or a mixture of potassiumchloride and either potassium acetate or sodium acetate.

Exemplary of formulations suitable for inhalation therapy include thoseformulations that can be administered from nebulizers of thesqueeze-bulb, reservoir, Venturi effect assembly, pressurized dispensersusing chloroflurohydrocarbon propellants, pre-micronized powders inliquid propellants, liquid-vapor phase aerosols, and the like.Typically, the formulation suitable for a conventional nebulizeroptionally is comprised of 0.4 to 0.8 percent solution of3,4-dipivaloxy-a -[isopropylamino)methyl]benzyl alcohol hydrogenchloride in a buffered carrier comprised of sodium chloride, sodiumcitrate, glycerine and a trace of preservative. In one embodiment theair in the dispenser can be displaced with nitrogen gas. A typicalpressurized dispenser can optionally be 0.20 to 0.50 percent on a weightby weight basis of 3,4-dipivaloxy-a -[(isopropylamine)methyl] benzylalcohol in a mixture of dichlorodifluoromethane anddichlorotetrafluoroethane with a sodium lactate lactic acid buffer,about 30 to 40 percent weight by weight of an alkanol and aromaticflavoring agents. Other formulations containing the compound of theinvention suspended in fluorochlorocarbons containing sorbitan trioleateand the like can also be used for administering the compound.

The dose administered, whether a single dose or a daily dose, will, orcourse, vary because of the chosen route of administration, and the sizeof the recipient. The dosage administered is not subject to definitebounds, but it will usually be an effective amount, or the equivalent ona molar basis of the pharmacologically active form produced upon themetabolic release of the active drug to achieve its desiredpharmacological and physiological effect. The medical dose forwarm-blooded mammals, including humans and primates by the intramuscularor subcutaneous route will be about 100 micrograms to milligramsadministered in 0.] to 1.5 ml ofa 0.1 to 0.5 percent oil suspension,with the usual intramuscular dose of 200 to 750 micrograms in 0.2 to0.75 ml ofa 0.1 to 0.5 percent solution. For oral inhalation the dose isabout 0.01 to 2.0 percent applied as a tine mist. For typicalapplication in operative procedures on the nose and throat, solutions of0.002 to 0.975 percent may be used. Generally, the dosage form for atypical non-toxic salt, for example, the hydrochloride in a solutionintended for inhalation will be about 0.025 to 4 percent and the like.The dose for farm animals is generally about 4 to 10 ml by-thesubcutaneous or intramuscular route for horses and cattle and for dogsabout 0.2 to 0.6 ml, and the like.

The unexpected, pronounced pharmacological properties for the compoundof the invention and its nontoxic salts are demonstrated by usingstandard art known testing procedures. For example, the antiasthmaticeffect of the compound of the invention is demonstrated as follows:first, adult, male guinea pigs are exposed to the nebulized spray of a0.2 percent weight by volume spray of 3,4-dihydroxy-a-[(isopropylamino)methyl]benzyl alcohol equivalent in saline solutionfor 2 minutes in an inhalation chamber. With the control animals, onlysaline solution is nebulized. Next the animals are exposed to ahistamine challenge 10 minutes after exposure to the various testedcompounds. The histamine challenge consists in exposing the animals tothe spray of a 0.2 percent weight by volume histamine diphosphatesolution, and then recording the time before the onset of the firstseiz'ure. All the compounds were tested on a 3,4-dihydroxy-oz -[(isopr-10 opylamino)methyl]benzyl alcohol basis, and the observed times are setforth in Table 1.

TABLE 1 Delay Before Onset Compound Of Seizure in Min.

Control 3,4-dihydroxy-a-[ isopropylamino 3.4-dipivaloxy-a-[isopropylamino methyllbenzyl alcohol hydrochloride 8 10 The enhancedstability of the compound is ascertained and compared against othercompounds by measuring its rate of hydrolysis in a pH 4.5 acetate buffersolution at room temperature and expressing the results as t days. Thetest solutions had a concentration of 0.5 milligrams per milliliter, andthe rate of hydrolysis was measured in a spectrophotometer at 280 mu.The results are set forth in Table 2. Also in the same table is setforth the rate of auto-oxidation of an 0.2 percent solution at a pH of 4in an air oxidative environment. These results are set forth as the timefor color formation, pink to brown, to develop in days from the firstexposure of the solution to the environment.

TABLE 2 Oxi- Hydrolysis dation Compound r Days3,4-dihydroxy-a-l(isopropylamino)- methyllbenzyl alcohol hydrochloridel5 3.4-diacetoxy-a-l(isopropylamino)- methyllbenzyl alcoholhydrochloride 30 20 3,4-dipropionoxy-a-l (isopropylam ino methyllbenzylalcohol hydrochloride 34 35 3,4-diisobutyroxy-a-l(isopropylaminomethyllbenzyl alcohol hydrochloride 50 353.4-dipivaloxy-a-[(isopropylamino)- methyllbenzyl alcohol hydrochloride700 300 The rate of cleavage of these compounds to the parent drug isdemonstrated in various biological media by measuring its enzymatic rateof hydrolysis in various media at 37C and expressing this result as thet seconds. The enzymatic rate of hydrolysis is measured at pH of about7.5 and at a concentration of 0.5 mg/ml of compound in media (a) horseserum cholinesterase, (b) rabbit serum, and (c) human plasma. Theresults for the compound are listed in Table 3, as are the results ofother compounds treated in a like enzymatic environment. The free basecompound was measured by using high pressure liquid chromatography.

TABLE 3 Rate of Hydrolysis in 2 Seconds What is claimed is: l. Acompound of the formula For example, the prior art compound can causeincreases in heart-rate and blood pressures when used as ananti-asthmatic, whereas, the compound of the invention has no sucheffects. The selectivity of the compound of the invention isdemonstrated as follows:

The test compound is administered as an intravenous solution or by meansof a nebulized mist. The observed heart-rate and blood pressures are setforth in Table 4 below:

or a pharmaceutically acceptable acid addition salt thereof.

2. A compound according to claim 1 wherein the compound is3,4-dipivaloxy-a -[(isopropylamino)methyl]benzyl alcohol.

3. A compound according to claim 1 wherein the compound is racemic3,4dipivaloxy-a -[(isopropylamino)methyl] benzyl alcohol.

4. A compound according to claim 1 which is an optical isomer of3,4-dipivaloxy a -[(isopropylamino)methyl]benzyl alcohol.

5. A pharmaceutical composition for treating asthma comprising aneffective amount of a member selected from the group consisting of3,4-dipivaloxy-a -[(iso propylamino)methyl] benzyl alcohol and itstherapeutically acceptable acid addition salts, admixed with apharmaceutically acceptable carrier.

6. A pharmaceutical composition according to claim 5 wherein the unitdosage amount consists of from 01 micrograms to 10 gramsof3,4-dipivaloxy-a -[(isopropylamino)methyl]benzyl alcohol admixed witha pharmaceutically acceptable carrier.

7. A pharmaceutical composition according to claim 5 wherein thecomposition consists of 0.01% to 2% of.

3,4-dipivaloxy-a-[(isopropylamino)methyl]benzyl alcohol and the carrieris a therapeutically acceptable inhalation carrier.

The above examples and disclosure are set forth merely for illustratingthe mode and the manner of the invention, and, while variousmodifications and embodiments can be made by those skilled in the art,in

the light of this invention, they are made without departing from thespirit of the invention. It is intended, therefore, that the inventionbe limited only by the scope of the claims which follow.

8. A method for relieving asthma in a warm-blooded animal which methodcomprises administering an inhalation composition comprising aninhalation vehicle and 0.01 to 2 percent of a member selected from thegroup consisting of 3,4-dipivaloxy-a- [(isopropylamino)methyllbenzylalcohol and a nontoxic acid addition salt thereof.

1. A COMPOUND OF THE FORMULA
 2. A compound according to claim 1 whereinthe compound is 3,4-dipivaloxy- Alpha -((isopropylamino)methyl)benzylalcohol.
 3. A compound according to claim 1 wherein the compound isracemic 3,4-dipivaloxy- Alpha -((isopropylamino)methyl) benzyl alcohol.4. A compound according to claim 1 which is an optical isomer of3,4-dipivaloxy Alpha -((isopropylamino)methyl) benzyl alcohol.
 5. Apharmaceutical composition for treating asthma comprising an effectiveamount of a member selected from the group consisting of 3,4-dipivaloxy-Alpha -((isopropylamino)methyl) benzyl alcohol and its therapeuticallyacceptable acid addition salts, admixed with a pharmaceuticallyacceptable carrier.
 6. A pharmaceutical composition according to claim 5wherein the unit dosage amount consists of from 0.1 micrograms to 10grams of 3,4-dipivaloxy- Alpha -((isopropylamino)methyl)benzyl alcoholadmixed with a pharmaceutically acceptable carrier.
 7. A pharmaceuticalcomposition according to claim 5 whereIn the composition consists of0.01% to 2% of 3,4-dipivaloxy- Alpha -((isopropylamino)methyl)benzylalcohol and the carrier is a therapeutically acceptable inhalationcarrier.
 8. A method for relieving asthma in a warm-blooded animal whichmethod comprises administering an inhalation composition comprising aninhalation vehicle and 0.01 to 2 percent of a member selected from thegroup consisting of 3,4-dipivaloxy-Alpha -((isopropylamino)methyl)benzylalcohol and a non-toxic acid addition salt thereof.